Title (eng)
Cell-autonomous IL6ST activation suppresses prostate cancer development via STAT3/ARF/p53-driven senescence and confers an immune-active tumor microenvironment
Author
Christina Sternberg
Martin Raigel
Tanja Limberger
Karolína Trachtová
Michaela Schlederer
Desiree Lindner
Petra Kodajova
Jiaye Yang
Roman Ziegler
Jessica Kalla
Stefan Stoiber
Saptaswa Dey
Daniela Zwolanek
Monika Oberhuber
Václav Hejret
Boris Tichy
Martina Tomberger
Nora S. Harbusch
Jan Pencik
Simone Tangermann
Vojtech Bystry
Jenny L Persson
Gerda Egger
Sarka Pospisilova
Robert Eferl
Peter Wolf
Felix Sternberg
Stefan Rose-John
Abstract (eng)
Prostate cancer ranks as the second most frequently diagnosed cancer in men worldwide. Recent research highlights the crucial roles IL6ST-mediated signaling pathways play in the development and progression of various cancers, particularly through hyperactivated STAT3 signaling. However, the molecular programs mediated by IL6ST/STAT3 in prostate cancer are poorly understood.To investigate the role of IL6ST signaling, we constitutively activated IL6ST signaling in the prostate epithelium of a Pten-deficient prostate cancer mouse model in vivo and examined IL6ST expression in large cohorts of prostate cancer patients. We complemented these data with in-depth transcriptomic and multiplex histopathological analyses.Genetic cell-autonomous activation of the IL6ST receptor in prostate epithelial cells triggers active STAT3 signaling and significantly reduces tumor growth in vivo. Mechanistically, genetic activation of IL6ST signaling mediates senescence via the STAT3/ARF/p53 axis and recruitment of cytotoxic T-cells, ultimately impeding tumor progression. In prostate cancer patients, high IL6ST mRNA expression levels correlate with better recurrence-free survival, increased senescence signals and a transition from an immune-cold to an immune-hot tumor.Our findings demonstrate a context-dependent role of IL6ST/STAT3 in carcinogenesis and a tumor-suppressive function in prostate cancer development by inducing senescence and immune cell attraction. We challenge the prevailing concept of blocking IL6ST/STAT3 signaling as a functional prostate cancer treatment and instead propose cell-autonomous IL6ST activation as a novel therapeutic strategy.
Keywords (eng)
Prostate CancerIL6ST/STAT3 SignalingL-gp130SenescenceSenescence-associated Secretory PhenotypeTumor MicroenvironmentImmune Cell InfiltrationCytotoxic T-Cells
Type (eng)
Language
[eng]
Persistent identifier
Is in series
Title (eng)
Molecular Cancer
Volume
23
Issue
1
ISSN
1476-4598
Issued
2024
Number of pages
22
Publication
BMC
Version type (eng)
Date issued
2024
Access rights (eng)
License
Rights statement (eng)
Copyright © 2024, The Author(s)
Citable links
Persistent identifier
https://phaidra.vetmeduni.ac.at/o:3743
https://doi.org/10.1186/s12943-024-02114-8
Content
Details
Object type
PDFDocument
Format
application/pdf
application/pdf
Created
10.12.2024 03:42:26
This object is in collection
Metadata
Export formats